Influence of host genetics and Mycobacterium tuberculosis strain variation on macrophage function and TB clinical outcome. (360G-Wellcome-097124_Z_11_Z)

The contribution of host genetics and Mtb strain variation to bacterial dissemination in TB are not fully understood. An impairment of macrophage function under the influence of these two factors may help explain the pathogenesis of TB and its different clinical presentations. This project has three key goals. 1) To determine whether host genetic variants of genes related to phagosomal function are associated with susceptibility to different clinical phenotypes of TB. Host genetic studies will be conducted using an existing case-control sample set in the Vietnamese population. 2) To investigate the association of macrophage function and TB outcomes. We will conduct ex-vivo studies on Mtb infected PBMC derived-macrophages and alveolar macrophages from subjects with different clinical phenotypes to determine phagosomal capacities. 3) To investigate the impact of Mtb lineage diversity on macrophage function in TB dissemination. We will examine variation in phagosomal activity between patients infected with the three major global lineages of Mtb common in Vietnam. Finally, results from the three areas above will be combined to obtain a comprehensive understanding of how the mutual interaction of host genetics, macrophage function and Mtb genotypes contribute to the development of different clinical forms of TB.